TGF-beta inducible early gene-1 (TIEG) is a member of the Kruppel-like transcription factor family originally cloned from human osteoblasts that is known to play an important role in transcriptional regulation and in TGF-beta mediated Smad signaling. TIEG is rapidly induced by estrogen in osteoblast cells and this induction seems to be specifically through the action of estrogen receptor-beta. Through the development and characterization of TIEG-null mice, we have shown that female animals display significantly weaker, smaller and less dense bones relative to wild-type litter mates. Intriguingly, these differences are not detectable in male animals implying a role for the sex steroids, in combination with the loss of TIEG expression, in the observed gender specific bone phenotype. Based on the above observations, it is the goal of this proposal to further characterize the molecular basis behind the gender specific bone phenotype, to identify the role of estrogen and/or testosterone in this gender specificity and to elucidate the mechanisms by which TIEG is specifically induced by estrogen receptor-beta. [unreadable] [unreadable] [unreadable]